Abstract Introduction: Patients (pts) with CLL who relapse on therapies targeting B-cell receptor signaling pathways have limited treatment options. Cerala, a selective oral ATR inhibitor, has shown synergistic preclinical activity with a Bruton tyrosine kinase inhibitor (BTKi) in TP53- and ATM-defective CLL cells (Kwok et al. Blood. 2016;127:582-95). Acala is a selective, irreversible BTKi approved for CLL. This phase 1/2 proof-of-concept study investigated cerala alone and in combination with acala in high-risk R/R CLL. Methods: This multicenter, nonrandomized, open-label study (NCT03328273) enrolled adults with high-risk R/R CLL per iwCLL criteria and ECOG performance status ≤2. In Arm A, pts with TP53 mutation, del(17p), or del(11q) having exhausted available treatment options received cerala monotherapy (cohort 1: 160 mg BID continuously; cohort 2 [after ≥2 DLTs in cohort 1]: 160 mg BID 2 wk on/2 wk off). In Arm B, pts with del(11q) suitable for BTKi and cerala treatment per investigator judgment received acala 100 mg BID continuously alone for cycle 1 and acala 100 mg BID continuously + cerala 160 mg BID 1 wk on/3 wk off from cycle 2 onward. Primary objectives: safety and pharmacokinetics (PK). Secondary objective: activity—overall response rate (ORR), complete response rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Pharmacodynamic changes were explored using novel multiple reaction monitoring-targeted mass spectrometry. Results: Eleven pts were treated (median age 64 y; median prior therapy lines 3). Pts in Arm A (n=8 [7 received prior BTKi]: cohort 1 n=5; cohort 2 n=3) received cerala for a median of 3.5 mo (range 0.5-7.7). Grade (G) ≥3 AEs in >1 pt were anemia (75%), thrombocytopenia (63%), and neutropenia (25%); 4 DLTs of G4 thrombocytopenia were reported (3 in 2 pts in cohort 1; 1 in 1 pt in cohort 2). No responses were observed in Arm A. At a median follow-up of 15.1 mo, median PFS was 3.8 mo (95% confidence interval [CI] 0.7-4.6); median OS was 16.9 mo (95% CI 6.6-not reached [NR]). All pts had baseline telomeres within a “fusogenic” range (negative prognostic indicator).In Arm B (n=3; all BTKi-naive), 2 pts received acala + cerala and 1 received acala only. Median (range) treatment duration was 7.2 mo (4.9-9.5) for cerala and 15.9 mo (9.7-18.4) for acala. No G≥3 AEs or DLTs were reported. ORR was 100% (all partial responses); median DOR was NR. At a median follow-up of 15.9 mo, median PFS and OS were NR. PK of acala and cerala were consistent with historical data, with no drug-drug interactions when combined; cerala did not affect BTK occupancy. Conclusions: Cerala monotherapy in BTKi-exposed, high-risk CLL pts showed limited clinical benefit. Acala + cerala was tolerable with preliminary clinical activity in pts with CLL and del(11q). The study terminated due to the evolving treatment landscape. Citation Format: Wojciech Jurczak, Nagah Elmusharaf, Christopher P. Fox, William Townsend, Amanda G. Paulovich, Shringi Sharma, Graeme Parr, Veerendra Munugalavadla, Fanny Krantz, Helen Yang, Emma Dean, Richa Manwani, Peter Hillmen. Phase 1/2 results of ceralasertib (Cerala) as monotherapy or in combination with acalabrutinib (Acala) in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT532.